Docetaxel targets aggressive methylation profiles and serves as a radiosensitizer in high-risk meningiomas.
Docetaxel targets aggressive methylation profiles and serves as a radiosensitizer in high-risk meningiomas.
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多西他赛针对侵袭性甲基化特征，并作为高风险脑膜瘤的放射增敏剂。
DOI：
10.1093/neuonc/noac206
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发表时间：
2023
期刊：
影响因子：
15.9
通讯作者：
Wang,
中科院分区：
文献类型：
--
作者：
Youngblood,MarkW;Tran,AnhN;Wang,Wenxia;An,Shejuan;Scholtens,Denise;Zhang,Lyndsee;O'Shea,Kaitlyn;Pokorny,JennyL;Magill,StephenT;Sachdev,Sean;Lukas,RimasV;Ahmed,Atique;Unruh,Dusten;Walshon,Jordain;McCortney,Kathleen;Wang,
背景脑膜瘤是成人最常见的原发性颅内肿瘤。这些肿瘤的一个子集复发并侵入大脑，即使在手术和放疗后，也会导致严重残疾。目前还没有脑膜瘤的标准治疗化疗。由于基因组DNA甲基化谱可以区分这些病变，我们试图确定是否有任何现有的化疗可能是有效的对脑膜瘤与高风险的methylation profiles.MethodsA以前发表的数据集脑膜瘤甲基化配置文件被用来筛选临床上显着的CpG甲基化事件和相关的细胞通路。基于这些结果，患者来源的脑膜瘤细胞系被用来测试候选药物在体外和体内，包括疗效与radiotherapy.ResultsWe确定了981个基因的甲基化映射的CpG位点与脑膜瘤的无进展生存。相关的分子途径与FDA批准的癌症药物交叉参考，该药物提名Docetamine作为进一步临床前分析的有希望的候选药物。多西他赛抑制了17种脑膜瘤细胞来源的生长，代表了所有肿瘤等级，临床上有利的IC 50值范围为0.3 nM至10.7 mM。这种药物的抑制作用与肿瘤倍增时间成比例，在快速生长的病变中获益最大。多西紫杉醇和放射治疗的结合增加了细胞凋亡和双链DNA断裂的标志物，并延长了移植脑膜瘤细胞的小鼠的生存期，相对于任一models.ConclusionsGlobal模式的DNA甲基化可能是有益的选择对脑膜瘤的化疗，现有的药物可以提高放射敏感性的高危病例。
BackgroundMeningioma is the most common primary intracranial tumor in adults. A subset of these tumors recur and invade the brain, even after surgery and radiation, resulting in significant disability. There is currently no standard-of-care chemotherapy for meningiomas. As genomic DNA methylation profiling can prognostically stratify these lesions, we sought to determine whether any existing chemotherapies might be effective against meningiomas with high-risk methylation profiles.MethodsA previously published dataset of meningioma methylation profiles was used to screen for clinically significant CpG methylation events and associated cellular pathways. Based on these results, patient-derived meningioma cell lines were used to test candidate drugsin vitroandin vivo, including efficacy in conjunction with radiotherapy.ResultsWe identified 981 genes for which methylation of mapped CpG sites was related to progression-free survival in meningiomas. Associated molecular pathways were cross-referenced with FDA-approved cancer drugs, which nominated Docetaxel as a promising candidate for further preclinical analyses. Docetaxel arrested growth in 17 meningioma cell sources, representing all tumor grades, with a clinically favorable IC50values ranging from 0.3 nM to 10.7 mM. The inhibitory effects of this medication scaled with tumor doubling time, with maximal benefit in fast-growing lesions. The combination of Docetaxel and radiation therapy increased markers of apoptosis and double-stranded DNA breaks, and extended the survival of mice engrafted with meningioma cells relative to either modality alone.ConclusionsGlobal patterns of DNA methylation may be informative for the selection of chemotherapies against meningiomas, and existing drugs may enhance radiation sensitivity in high-risk cases.